The amino acid glutamine is the primary nutrient for the intestinal enterocytes and thus, critical for the health of the epithelium. However, how glutamine is assimilated in the normal mammalian small intestine and/or in a primarily mucosal disease such as inflammatory bowel disease (IBD) is not well known. Glutamine is absorbed via Na- glutamine co-transport (NGcT) on the brush border membrane (BBM) of enterocytes. We have demonstrated that B0AT1 mediates NGcT on the BBM of villus cells. And in paradigm shift, we demonstrated the only nutrient absorptive process on the BBM of crypt cells, specifically SN2, which mediates NGcT in these cells. Further, in a rabbit model of chronic intestinal inflammation resembling IBD we demonstrated that NGcT in total was reduced. This net inhibition was a sum of B0AT1 inhibition in villus cells and SN2 stimulation in crypt cells. The mechanism of inhibition of B0AT1 was secondary to a reduction in the number of co-transporters in the villus cell BBM while the mechanism of stimulation of SN2 in crypt cells was secondary to an increase in the affinity for glutamine. Thus, glutamine assimilation which occurs via distinct transporters in villus and crypt cells is uniquely regulated in the chronically inflamed intestine. Importantly, similar results were seen in the human IBD intestine. Additional preliminary studies indicated that immune inflammatory mediators known to be produced in the chronically inflamed intestine may be responsible for these unique alterations in glutamine absorption. Given this background, the overall aim is to determine the immune mechanism of regulation of B0AT1 in villus and SN2 in crypt cells in the chronically inflamed intestine. Better understanding of the regulation of glutamine absorption in the normal and IBD intestine will provide the foundation to develop more efficacious, specific immune based nutritional therapies for IBD.